Malignant cell behavior can arise by several mechanisms but is frequently associated with amplified activities of receptor tyrosine kinases and downstream signaling cascades. These pathways have been linked to anchorage-independent growth, to invasiveness and to multidrug resistance, common properties of malignant cancer cells. Drug resistance is also associated with enhanced drug efflux via ATP-dependent, ABC family transporters, and recent work emphasizes a potential role for cancer progenitor/ "side population" cells enriched in the ABCG2 transporter in resistance. Close regulatory connections have now been revealed between all of these cellular properties and hyaluronan, a major component of the pericellular matrix surrounding tumor cells in vivo. Emmprin (CD 147), a cell surface glycoprotein enriched in malignant tumor cells, induces hyaluronan synthesis and its effects. Thus the long-term objective of this work is to determine the mechanisms whereby hyaluronan and emmprin regulate these hallmark properties of malignant cells as a basis for designing therapeutic interventions in cancer patients. A central question addressed in this proposal is how hyaluronan signaling becomes activated in malignant cells. Chronic inflammation and associated alterations in the stromal microenvironment of tumors induce or enhance malignant cell properties and tumor progression. In particular, tumor-associated macrophages promote signaling pathways linked to tumor cell survival, invasiveness and multidrug resistance. Both hyaluronan and emmprin are now known to be crucial components of inflammatory processes. The novel hypothesis guiding the proposed work is that mediators produced by cells in the stromal microenvironment, especially macrophages, induce hyaluronan-dependent signaling and consequent malignant outcomes, such as resistance to apoptosis/ drug resistance in tumor cells. The proposed studies address this question in macrophage-tumor co-culture systems, in drug-resistant side population cells and in animal models. These experiments will help illuminate the mechanisms whereby hyaluronan-induced receptor tyrosine kinase signaling is initiated in cancer cells and results in malignant cell properties, especially drug resistance and its relationship to cancer progenitor cells. Consequently, these approaches will help to guide further development of therapeutic interventions in cancer patients, employing antagonists of deregulated HA interactions.